Hepatitis B is the most prevalent form of hepatitis and is the second most common infectious disease worldwide. Worldwide estimates of those chronically infected with hepatitis B virus (HBV) are in excess of 300,000,000. The disease is caused by the hepatitis B virus, a DNA virus. The virus is transmitted through blood transfusions, contaminated needles, sexual contact and vertical transmission from mother to child. Moreover, a significant number of people are infected by unknown means.
Carriers of the virus can exhibit various forms of disease, one of which is chronic hepatitis B. Approximately 50% of the carriers show chronic inflammatory changes in the liver and, of these, about 50% have histopathologic changes, which are termed "chronic active hepatitis", that may lead to fibrosis and ultimately to cirrhosis and progressive liver failure. Carriers without chronic inflammatory changes may also develop chronic active hepatitis. Liver cancer develops in about 10 to 30% of hepatitis B carriers. It has been estimated that approximately 4 million carriers of hepatitis B virus die each year from liver cancer or cirrhosis.
The persistent infection seen in individuals exhibiting chronic hepatitis may be due to a defective or physiologically immature immunological response, resulting in an impaired ability to clear the virus. Although the mechanisms responsible for liver damage are poorly understood, it is thought that in most individuals such damage results from attack by the body's immune system on infected liver cells, rather than from liver destruction by HBV. Cytotoxic T cells appear to be responsible for immune-mediated hepatic damage. The balance between suppression of immune system activity against normal tissue and the immunological response mounted against the virus, also appears to be impaired in chronic hepatitis B. A number of specific immune defects have been described in chronic hepatitis, including defective production of alpha-interferon by HBV-infected hepatocytes and inhibition of cytotoxic T cell responses. (reviewed in Peters, M. et al., Hepatology (United States) (May 1991) 13(5):977-94).
Chronic infection is manifested by persistence of hepatitis B surface antigen (HB.sub.s Ag) in the serum for more than 6 months. The presence of hepatitis B.sub.e antigen (HB.sub.e Ag) is associated with high levels of viral replication.
The goals of treatment in chronic HBV infection include sustained reduction of HBV replication (loss of HB.sub.e Ag and HBV DNA), loss of HB.sub.s Ag, diminished infectivity, normalization of aminotransferase levels, resolution of hepatic inflammation, improvement in symptoms, and a decreased rate of liver disease progression. The disappearance of HB.sub.s Ag from serum, implying termination of the HBV carrier state, has been difficult to achieve with antiviral therapy.
Recent therapeutic trials have been directed towards utilization of anti-viral agents, immunomodulators, immunosuppressives or combinations of these. See, e.g. Thomas, H. C. et al., Seminars in Liver Disease (1986) 6(1): 34-41; Alexander, G. J. M. et al., Am. J. Med. (1988) 85: 143-146; Aach, R. D. et al., Ann. Int. Med. (1988) 109: 89-91. At present, alpha-interferon is the only therapeutic approach that has had regulatory approval in a number of countries. Interferon, however, induces a response in less than 50% of patients with chronic hepatitis B, and has significant side effects that sometimes lead to early cessation of therapy. Such side effects include fever, chills, and headaches, followed by fatigue, anorexia, weight loss, emotional disturbances and in some cases, bone marrow suppression. (Perrillo, R. P. et al., Ann. Int. Med. (1988) 109: 95-100; Hoofnagle, J. H. et al., Gastroenterology (1988) 95: 1318-1325. Other reported side effects include rigors, alopecia, nausea and vomiting.
Various antiviral agents have been used as sole therapy agents in an attempt to treat chronic hepatitis B infection, including acyclovir, vidarabine, and adenine arabinoside. Sole therapy with these antiviral agents generally has been unsuccessful, either because the agent was highly toxic or resulted in some inhibition of viral replication initially, but failed to sustain viral replication inhibition long-term. See e.g. Alexander, G. J. M. et al., American J. Med. (1988), 85-2A: 143-146.
Thymosin alpha-1 is a 28 amino acid peptide. The peptide, originally isolated from calf thymus thymosin fraction 5, is one of several polypeptides present in thymosin fraction 5 which participate in the regulation, differentiation and function of thymic dependent lymphocytes (T-cells). The isolation, characterization and use of thymosin alpha-1 is described, for example, in U.S. Pat. No. 4,079,127.
Although the mechanism(s) by which thymosin alpha-1 mediates its effects is unknown, evidence suggests that it may function through modulation of the immune system. Thymosin alpha-l has been shown to cause increases in lymphocyte counts and enhance production of gamma-interferon in individuals suffering from chronic active hepatitis B (Mutchnick, M. G. et al., Hepatology (1991) 14: 409-415).
Mutchnick, M. G. et al., "Thymosin: An Innovative Approach to the Treatment of Chronic Hepatitis B", in Combination Therapies, Garaci, E., Plenum Press, New York 1992, pps. 149-157, also describes the use of thymosin alpha-1 in the treatment of chronic active hepatitis B, that is, patients with evidence of liver injury upon biopsy. In 75% of the patients in the study who received the peptide cleared hepatitis B virus DNA from serum and persistently tested negative for serum HBV DNA after treatment was terminated.
There remains an important need for a therapy for chronic hepatitis B that efficiently and with fewer side effects attacks the virus and modulates the immune response system.